Abstract
ObjectiveThe predictors of Fanconi syndrome (FS) accompanied by renal function decline with use of the antiretroviral tenofovir disoproxil fumarate (TDF) have not been assessed. In addition, the natural history of renal recovery from FS after TDF discontinuation is not well-described.DesignWe prospectively enrolled HIV-infected patients receiving TDF with newly identified FS (defined as at least two markers of proximal tubulopathy and either a >25% decline in creatinine clearance (CrCl) from pre-TDF values or a CrCl <60 mL/min in those without a known pre-TDF CrCl) in a multicenter observational study. These case participants were matched 1∶2 to controls; characteristics between the two groups were compared. Case participants with known pre-TDF CrCl values were then followed over 48 weeks to assess renal recovery.ResultsNineteen cases and 37 controls were enrolled. In multivariable analysis, previous or concurrent use of lopinavir/ritonavir [OR 16.37, 95% CI (2.28, 117.68); P = 0.006] and reduced creatinine clearance prior to initiation of TDF [OR 1.44 for every 5 mL/min reduction, 95% CI (1.09, 1.92); P = 0.012; OR 19.77 for pre-TDF CrCl lower than 83 mL/min, 95% CI (2.24, 174.67); P = 0.007] were significantly associated with FS. Of the 14 cases followed for resolution, 7 (50%) achieved at least partial resolution (defined as recovering CrCl >70% of pre-TDF values) although most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation.ConclusionsFS, defined by specific CrCl decreases and markers of tubulopathy, is more likely in those who have received or are currently receiving concomitant lopinavir/ritonavir or who had lower CrCl prior to TDF initiation. Half of those with protocol-defined FS had CrCl recover to near pre-TDF values during the first year after TDF discontinuation.
Highlights
The use of tenofovir disoproxil fumarate (TDF) is recommended as a component of all first-line treatment regimens in antiretroviral (ART)-naıve, HIV-infected patients due to its high virologic efficacy and good tolerability [1,2]
Previous or concurrent use of lopinavir/ ritonavir [OR 16.37, 95% CI (2.28, 117.68); P = 0.006] and reduced creatinine clearance prior to initiation of TDF [OR 1.44 for every 5 mL/min reduction, 95% CI (1.09, 1.92); P = 0.012; OR 19.77 for pre-TDF CrCl lower than 83 mL/min, 95% CI (2.24, 174.67); P = 0.007] were significantly associated with Fanconi syndrome (FS)
Of the 14 cases followed for resolution, 7 (50%) achieved at least partial resolution most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation
Summary
The use of tenofovir disoproxil fumarate (TDF) is recommended as a component of all first-line treatment regimens in antiretroviral (ART)-naıve, HIV-infected patients due to its high virologic efficacy and good tolerability [1,2]. With the widespread use of TDF, reports of nephrotoxicity, including renal proximal tubulopathy (or Fanconi syndrome), have been published [3]. The overall incidence of Fanconi syndrome (FS), especially when accompanied by clinically relevant reductions in renal function, remains low [4,5]. This suggests there may be specific predisposing factors that put certain patients at risk for more severe forms of TDF-related renal toxicity. A comprehensive assessment of potential risk factors would be clinically useful to identify those patients for whom FS with actual renal function decline is more likely to occur. It would be valuable to describe the time to resolution of this type of FS in order to provide clinicians and patients with a better understanding of the natural time course of renal improvement, if any, once TDF is withdrawn, especially as recent reports suggest that full resolution is not universal [11,12]
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